New use

ABSTRACT

According to the invention there is provided a kit of parts comprising: (a) a pharmaceutical formulation including a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including a prodrug of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of that prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other, as well as the use of such a kit of parts in the treatment of a condition in which inhibition of thrombin is required or desired.

FIELD OF THE INVENTION

This invention relates to a new use of low molecular weight thrombininhibitors.

BACKGROUND AND PRIOR ART

Blood coagulation is the key process involved in both haemostasis (i.e.the prevention of blood loss from a damaged vessel) and thrombosis (i.e.the formation of a blood clot in a blood vessel, sometimes leading tovessel obstruction).

Coagulation is the result of a complex series of enzymatic reactions.One of the ultimate steps in this series of reactions is the conversionof the proenzyme prothrombin to the active enzyme thrombin.

Thrombin is known to play a central role in coagulation. It activatesplatelets, leading to platelet aggregation, converts fibrinogen intofibrin monomers, which polymerise spontaneously into fibrin polymers,and activates factor XIII, which in turn crosslinks the polymers to forminsoluble fibrin. Furthermore, thrombin activates factor V and factorVIII leading to a “positive feedback” generation of thrombin fromprothrombin.

Effective inhibitors of thrombin are thus known, and/or are expected, tobe useful as anticoagulants and therefore useful in the therapeutictreatment of thrombosis and related disorders.

The early development of low molecular weight inhibitors of thrombin hasbeen described by Claesson in Blood Coagul. Fibrinol. (1994) 5, 411. Lowmolecular weight thrombin inhibitors have been described more recentlyin U.S. Pat. No. 4,346,078; International Patent Applications WO93/11152, WO 93/18060, WO 93/05069, WO 94/20467, WO 94/29336, WO95/35309, WO 95/23609, WO 96/03374, WO 96/06832, WO 96/06849, WO96/25426, WO 96/32110, WO 97/01338, WO 97/02284, WO 97/15190, WO97/30708, WO 97/40024, WO 97/46577, WO 98/06740, WO 97/49404, WO97/11693, WO 97/24135, WO 97/47299, WO 98/01422, WO 98/57932, WO99/29664, WO 98/06741, WO 99/37668, WO 99/37611, WO 98/37075, WO99/00371, WO 99/28297, WO 99/29670, WO 99/40072, WO 99/54313, WO96/31504, WO 00/01704 and WO 00/08014; and European Patent Applications648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212,362 002, 364 344, 530 167, 293 881, 686 642, 669 317, 601 459 and 623596.

In particular, international patent application WO 94/29336 discloses agroup of compounds, including HOOC—CH₂—(R)Cgl-Aze-Pab-H (in which Cglrepresents cyclohexylglycine, Aze represents S-azetidine-2-carboxylicacid and Pab-H represents 4-aminomethyl-amidinobenzene), which is alsoknown as melagatran (see Example 1 of WO 94/29336). International PatentApplication WO 97/23499 discloses prodrugs of inter alia melagatran.

None of the above-mentioned documents disclose or suggest theadministration of an active thrombin inhibitor in conjunction with aprodrug of that thrombin inhibitor, or indeed in conjunction with aprodrug of any thrombin inhibitor.

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are majorhealth problems, which may give rise to serious outcomes. In particular,PE may be fatal, or may result in the development of pulmonaryhypertension and heart failure from recurrent embolism. DVT may resultin post-thrombotic venous insufficiency and ulcers in the affected partof the body (e.g. leg). Both are common conditions, which have a greatimpact on worldwide healthcare costs.

There is a considerable incidence of DVT and PE following orthopaedicsurgery. For example, in patients undergoing total hip replacement, theincidence of DVT in the absence of thromboprophylaxis may be as high as45 to 57%. Further, the incidence of proximal DVT may be between 23 and36%, and that of fatal PE, 0.34 to 6%. In patients undergoing total kneereplacement in the absence of thromboprophylaxis, the postoperativeincidence of DVT is between 40 and 84%, of proximal DVT is between 9 and20%, and of fatal PE is between 0.2 and 0.7%. In patients undergoinggeneral surgery in the absence of thromboprophylaxis, the postoperativeincidence of DVT is about 25%. (Reference: Chest (1998) 114, 531S to560S.)

Low-dose, subcutaneous (s.c.) unfractionated heparin is the most widelyused current prophylactic treatment for venous thromboembolism resultingfrom orthopaedic and general surgery. The incidence of DVT after totalhip replacement has been shown to be reduced (see Chest referenceabove).

The use of low-molecular weight heparin (LMWH) in the prophylaxis of DVTfollowing total hip and knee replacement operations has been shown tofurther the reduce incidence (when compared to low dose unfractionatedheparin), without a concomitant increase in bleeding (see Chestreference above).

However, prolonged treatment with heparins has been shown to give riseto an increased risk of osteoporosis. Heparins may also give rise to“heparin-induced thrombocytopenia” (HIT), are dependent on the plasmalevel of the endogenous thrombin inhibitor, antithrombin, and do notinactivate clot-bound thrombin.

Oral anticoagulants, such as warfarin (a vitamin K antagonist), has alsobeen shown to be effective in reducing DVT after major surgery (seeChest reference above). However, due to the risk of bleeding, and theneed for frequent laboratory control, the use of this substance isgenerally reserved for high risk patients, and/or for long term use.Vitamin K antagonists also demonstrate a notable risk of interactionwith other drugs and certain foods, and their use requires monitoring ofthe patient's blood coagulation status.

Antiplatelet agents, such as aspirin, have been shown to have limitedefficacy in preventing DVT (see Chest reference above).

Comparative clinical studies carried out during the course of total hipreplacement operations have shown that subcutaneous administration ofthe thrombin inhibitor hirudin is superior to unfractionated heparin andLMWH in reducing the frequency of total and proximal DVT with nocorresponding increase in bleeding (see Eriksson et al in Lancet, 347,635 (1996) and J. Bone Joint. Surg., September 11 (1996)). However,hirudin is expensive and has an immunogenic potential.

Thus, there is a need for effective treatments of thrombotic conditionssuch as DVT.

DISCLOSURE OF THE INVENTION

We have found, surprisingly, that administration of a low molecularweight thrombin inhibitor in conjunction with a prodrug of a (or aprodrug of that) thrombin inhibitor gives rise to a notableanticoagulant effect.

According to a first aspect of the invention there is provided a kit ofparts comprising components:

-   -   (a) a pharmaceutical formulation including a low molecular        weight thrombin inhibitor, or a pharmaceutically acceptable        derivative thereof, in admixture with a pharmaceutically        acceptable adjuvant, diluent or carrier; and    -   (b) a pharmaceutical formulation including a prodrug of a low        molecular weight thrombin inhibitor, or a pharmaceutically        acceptable derivative of that prodrug, in admixture with a        pharmaceutically acceptable adjuvant, diluent or carrier,        which components (a) and (b) are each provided in a form that is        suitable for administration in conjunction with the other.

It is preferred that the prodrug of component (b) is a prodrug of theactive low molecular weight thrombin inhibitor of component (a).

According to a further aspect of the invention, there is provided amethod of making a kit of parts as defined herein, which methodcomprises bringing a component (a), as defined above, into associationwith a component (b), as defined above, thus rendering the twocomponents suitable for administration in conjunction with each other.By bringing the two components “into association with” each other, weinclude that components (a) and (b) may be:

-   -   (i) provided as separate formulations (i.e. independently of one        another), which are subsequently brought together for use in        conjunction with each other in combination therapy; or    -   (ii) packaged and presented together as separate components of a        “combination pack” for use in conjunction with each other in        combination therapy.

Thus, there is further provided a kit of parts comprising:

-   -   (1) one of components (a) and (b) as defined herein; together        with    -   (2) instructions to use that component in conjunction with the        other of the two components.

The kits of parts defined herein may comprise more than one formulationincluding an appropriate quantity/dose of thrombin inhibitor, and/ormore than one formulation including an appropriate quantity/dose ofrespective prodrug, in order to provide for repeat dosing. If more thanone formulation (comprising thrombin inhibitor or prodrug) is present,such formulations may be the same, or may be different in terms of thedose of thrombin inhibitor/prodrug, chemical composition and/or physicalform.

A further aspect of the invention provides a method of treatment of acondition in which inhibition of thrombin is required or desired, whichcomprises administration of:

-   -   (a) a pharmaceutical formulation including a low molecular        weight thrombin inhibitor, or a pharmaceutically acceptable        derivative thereof, in admixture with a pharmaceutically        acceptable adjuvant, diluent or carrier; in conjunction with    -   (b) a pharmaceutical formulation including a prodrug of a low        molecular weight thrombin inhibitor, or a pharmaceutically        acceptable derivative of that prodrug, in admixture with a        pharmaceutically acceptable adjuvant, diluent or carrier,        to a patient suffering from, or susceptible to, such a        condition.

For the avoidance of doubt, as used herein, the term “treatment”includes therapeutic and/or prophylactic treatment.

“Pharmaceutically acceptable derivatives” of thrombin inhibitors andprodrugs includes salts, (e.g. pharmaceutically acceptable non-toxicorganic or inorganic acid addition salts) and solvates. It will beappreciated that the term pharmaceutically acceptable derivatives ofactive thrombin inhibitors includes those derivatives that have the samebiological function and/or activity as that thrombin inhibitor but, forthe purposes of this invention, does not include prodrugs of thatthrombin inhibitor.

By “administration in conjunction with”, we include that respectiveformulations comprising thrombin inhibitor and/or prodrug areadministered, sequentially, separately and/or simultaneously, over thecourse of treatment of the relevant condition, which condition may beacute or chronic. Preferably, the term includes that the twoformulations are administered (optionally repeatedly) sufficientlyclosely in time for there to be a beneficial effect for the patient,that is greater, over the course of the treatment of the relevantcondition, than if either of the two formulations are administered(optionally repeatedly) alone, in the absence of the other formulation,over the same course of treatment. Determination of whether acombination provides a greater beneficial effect in respect of, and overthe course of treatment of, a particular condition, will depend upon thecondition to be treated or prevented, but may be achieved routinely bythe skilled person.

Thus, the term “in conjunction with” includes that one or other of thetwo formulations may be administered (optionally repeatedly) prior to,after, and/or at the same time as, administration with the othercomponent. When used in this context, the terms “administeredsimultaneously” and “administered at the same time as” include thatindividual doses of thrombin inhibitor and prodrug are administeredwithin 48 hours (e.g. 24 hours) of each other.

Components (a) and (b) as described herein may also be presented (i.e.formulated) as a combined preparation (i.e. presented as a singleformulation including low molecular thrombin inhibitor and prodrug).

Thus, there is further provided a pharmaceutical formulation including alow molecular weight thrombin inhibitor (or a pharmaceuticallyacceptable derivative thereof) and a prodrug of a low molecular weightthrombin inhibitor (or a pharmaceutically acceptable derivative of thatprodrug), in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier.

The term “low molecular weight thrombin inhibitor” will be understood bythose skilled in the art. The term may also be understood to include anycomposition of matter (e.g. chemical compound) which inhibits thrombinto an experimentally determinable degree in in vivo and/or in in vitrotests, and which possesses a molecular weight of below 2,000, preferablybelow 1,000.

Preferred low molecular weight thrombin inhibitors include low molecularweight peptide-based, amino acid-based, and/or peptide analogue-based,thrombin inhibitors.

The term “low molecular weight peptide-based, amino acid-based, and/orpeptide analogue-based, thrombin inhibitors” will be well understood byone skilled in the art to include low molecular weight thrombininhibitors with one to four peptide linkages, and includes thosedescribed in the review paper by Claesson in Blood Coagul. Fibrin.(1994) 5, 411, as well as those disclosed in U.S. Pat. No. 4,346,078;International Patent Applications WO 93/11152, WO 93/18060, WO 93/05069,WO 94/20467, WO 94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO96/06832, WO 96/06849, WO 96/25426, WO 96/32110, WO 97/01338, WO97/02284, WO 97/15190, WO 97/30708, WO 97/40024, WO 97/46577, WO98/06740, WO 97/49404, WO 97/11693, WO 97/24135, WO 97/47299, WO98/01422, WO 98/57932, WO 99/29664, WO 98/06741, WO 99/37668, WO99/37611, WO 98/37075, WO 99/00371, WO 99/28297, WO 99/29670, WO99/40072, WO 99/54313, WO 96/31504, WO 00/01704 and WO 00/08014; andEuropean Patent Applications 648 780, 468 231, 559 046, 641 779, 185390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686642, 669 317, 601 459 and 623 596, the disclosures in all of whichdocuments are hereby incorporated by reference.

Preferred low molecular weight peptide-based thrombin inhibitors includeHOOC—CH₂—(R)Cha-Pic-Nag-H (wherein Cha represents cyclohexylalanine, Picrepresents (S)-pipecolinic acid and Nag represents noragmatine; known asinogatran; see International Patent Application WO 93/11152) and,especially, HOOC—CH₂—(R)Cgl-Aze-Pab-H (known as melagatran; see aboveand International Patent Application WO 94/29336).

The term “prodrug” of a low molecular weight thrombin inhibitor includesany compound that, following oral or parenteral administration, ismetabolised in vivo to form a low molecular weight thrombin inhibitor(as defined herein), in an experimentally-detectable amount, and withina predetermined time (e.g. within a dosing interval of between 6 and 24hours (i.e. once to four times daily)), following oral or parenteraladministration. Prodrugs of the thrombin inhibitor melagatran that maybe mentioned include those disclosed in international patent applicationWO 97/23499. Preferred prodrugs are those of the formulaR¹O₂C—CH₂—(R)Cgl-Aze-Pab-OH (see the list of abbreviations above or inWO 97/23499), wherein R¹ represents C₁₋₁₀ alkyl or benzyl, such aslinear or branched C₁₋₆ alkyl (e.g. C₁₋₄ alkyl, especially methyl,propyl and, particularly, ethyl) and the OH group replaces one of theamidino hydrogens in Pab.

The term “condition in which inhibition of thrombin is required ordesired” will be understood by those skilled in the art to include thefollowing:

The treatment and/or prophylaxis of thrombosis and hypercoagulability inblood and tissues of animals including man. It is known thathypercoagulability may lead to thrombo-embolic diseases. Conditionsassociated with hypercoagulability and thrombo-embolic diseases whichmay be mentioned include inherited or acquired activated protein Cresistance, such as the factor V-mutation (factor V Leiden), andinherited or acquired deficiencies in antithrombin III, protein C,protein S, heparin cofactor II. Other conditions known to be associatedwith hypercoagulability and thrombo-embolic disease include circulatingantiphospholipid antibodies (Lupus anticoagulant), homocysteinemi,heparin induced thrombocytopenia and defects in fibrinolysis.

The treatment of conditions where there is an undesirable excess ofthrombin without signs of hypercoagulability, for example inneurodegenerative diseases such as Alzheimer's disease.

Particular disease states which may be mentioned include the therapeuticand/or prophylactic treatment of venous thrombosis (e.g. DVT) andpulmonary embolism, arterial thrombosis (e.g. in myocardial infarction,unstable angina, thrombosis-based stroke and peripheral arterialthrombosis) and systemic embolism usually from the atrium duringarterial fibrillation or from the left ventricle after transmuralmyocardial infarction, or caused by congestive heart failure;prophylaxis of re-occlusion (ie thrombosis) after thrombolysis,percutaneous trans-luminal angioplasty (PTA) and coronary bypassoperations; the prevention of re-thrombosis after microsurgery andvascular surgery in general.

Further indications include the therapeutic and/or prophylactictreatment of disseminated intravascular coagulation caused by bacteria,multiple trauma, intoxication or any other mechanism; anticoagulanttreatment when blood is in contact with foreign surfaces in the bodysuch as vascular grafts, vascular stents, vascular catheters, mechanicaland biological prosthetic valves or any other medical device; andanticoagulant treatment when blood is in contact with medical devicesoutside the body such as during cardiovascular surgery using aheart-lung machine or in haemodialysis; the therapeutic and/orprophylactic treatment of idiopathic and adult respiratory distresssyndrome, pulmonary fibrosis following treatment with radiation orchemotherapy, septic shock, septicemia, inflammatory responses, whichinclude, but are not limited to, edema, acute or chronic atherosclerosissuch as coronary arterial disease, cerebral arterial disease, peripheralarterial disease, reperfusion damage, and restenosis after percutaneoustrans-luminal angioplasty (PTA).

Preferred conditions include thrombosis, especially DVT, includingdistal and proximal DVT. The present invention finds particular utilityin the prophylactic treatment of DVT resulting from surgery, such asgastrointestinal, or orthopaedic, surgery (e.g. hip or kneereplacement). This includes DVT resulting from immobilisation aftersurgery.

In accordance with the invention, thrombin inhibitors, prodrugs ofthrombin inhibitors, and derivatives of either, may be administeredorally, intravenously, subcutaneously, buccally, rectally, dermally,nasally, tracheally, bronchially, topically, by any other parenteralroute, or via inhalation, in the form of a pharmaceutical preparationcomprising the thrombin inhibitor or prodrug in a pharmaceuticallyacceptable dosage form. Depending on the disorder, and the patient, tobe treated, as well as the route of administration, the compositions maybe administered at varying doses.

Preferred modes of delivery are systemic. For melagatran and derivativesthereof, preferred modes of administration are parenteral, morepreferably intravenous, and especially subcutaneous. For prodrugs ofmelagatran, preferred modes of administration are oral.

In the therapeutic treatment of mammals, and especially humans, thrombininhibitors, prodrugs of thrombin inhibitors, and derivatives of eitherwill generally be administered as a pharmaceutical formulation inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier, which may be selected with due regard to the intended route ofadministration and standard pharmaceutical practice.

Suitable formulations for use in administering thrombin inhibitors areknown in the art, and include those known from U.S. Pat. No. 4,346,078;International Patent Applications WO 93/11152, WO 93/18060, WO 93/05069,WO 94/20467, WO 94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO96/06832, WO 96/06849, WO 96/25426, WO 96/32110, WO 97/01338, WO97/02284, WO 97/15190, WO 97/30708, WO 97/40024, WO 97/46577, WO98/06740, WO 97/49404, WO 97/11693, WO 97/24135, WO 97/47299, WO98/01422, WO 98/57932, WO 99/29664, WO 98/06741, WO 99/37668, WO99/37611, WO 98/37075, WO 99/00371, WO 99/28297, WO 99/29670, WO99/40072, WO 99/54313, WO 96/31504, WO 00/01704 and WO 00/08014; andEuropean Patent Applications 648 780, 468 231, 559 046, 641 779, 185390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686642, 669 317, 601 459 and 623 596, the disclosures in all of whichdocuments are hereby incorporated by reference.

Suitable formulations for use with melagatran, derivatives and prodrugsthereof are described in the literature, for example as described ininter alia international patent applications WO 94/29336, WO 96/14084,WO 96/16671, WO 97/23499, WO 97/39770, WO 97/45138, WO 98/16252, WO99/27912 and WO 99/27913, the disclosures in which documents are herebyincorporated by reference. Otherwise, the preparation of suitableformulations may be achieved non-inventively by the skilled person usingroutine techniques.

The amounts of thrombin inhibitor, prodrug, or derivative of either, inthe formulation will depend on the severity of the condition, and on thepatient, to be treated, as well as the compound(s) which is/areemployed, but may be determined non-inventively by the skilled person.

Suitable doses of thrombin inhibitors, prodrugs and derivatives ofeither, in the therapeutic and/or prophylactic treatment of mammalian,especially human, patients may be determined routinely by the medicalpractitioner or other skilled person, and include the respective dosesdiscussed in the prior art documents disclosing thrombin inhibitors thatare mentioned hereinbefore, the disclosures in which are herebyincorporated by reference.

In the case of melagatran, suitable doses of active compound, prodrugsand derivatives thereof, in the therapeutic and/or prophylactictreatment of mammalian, especially human, patients include those whichgive a mean plasma concentration of up to 5 μmol/L, for example in therange 0.001 to 5 μmol/L over the course of treatment of the relevantcondition. Suitable doses may thus be in the range 0.1 mg once daily to25 mg three times daily, and/or up to 100 mg infused parenterally over a24 hour period, for melagatran, and in the range 0.1 mg once daily to100 mg three times daily for prodrugs of melagatran including thosespecifically mentioned hereinbefore.

In any event, the physician, or the skilled person, will be able todetermine the actual dosage which will be most suitable for anindividual patient, which is likely to vary with the condition that isto be treated, as well as the age, weight, sex and response of theparticular patient to be treated. The above-mentioned dosages areexemplary of the average case; there can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

The sequence in which the formulations comprising thrombin inhibitor,and prodrug, may be administered (i.e. whether, and at what point,sequential, separate and/or simultaneous administration takes place) maybe determined by the physician or skilled person. For example, thesequence may depend upon many factors that will be evident to theskilled person, such as whether, at any time during the course or periodof treatment, one or other of the formulations cannot be administered tothe patient for practical reasons (e.g. the patient is unconscious andthus unable to take an oral formulation comprising either thrombininhibitor or prodrug).

For example, in the treatment of thrombosis (e.g. DVT) resulting fromsurgery, such as gastrointestinal, or orthopaedic, surgery, and when theactive thrombin inhibitor is melagatran, it is preferred that theformulation comprising melagatran is administered parenterally withintwo days (e.g. within 24 hours) of surgery (either prior to or aftersurgery), and particularly immediately prior to (e.g. within 2 hours),and/or within up to 12 hours after, surgery (e.g. at least one hourafter surgery), and thereafter for up to between 3 and 7 (e.g. between 0and 2, such as between 1 and 2) days after that surgery, and that theformulation comprising prodrug is administered orally within 7 daysfollowing that surgery (preferably once administration of melagatran hasbeen terminated) for up to e.g. between 11 and 40 days, preferably 9days, more preferably up to 8 days.

The method described herein may have the advantage that, in thetreatment of conditions in which inhibition of thrombin is required ordesired, it may be more convenient for the physician and/or patientthan, be more efficacious than, be less toxic than, have a broader rangeof activity than, be more potent than, produce fewer side effects than,or that it may have other useful pharmacological properties over,similar methods known in the prior art for the treatment of suchconditions.

The invention is illustrated, but in no way limited, by the followingexample.

EXAMPLE 1 Clinical Trial—Melagatran and EtOOC—CH₂—(R)Cgl-Aze-Pab-OHCombination Therapy

A controlled, randomised, parallel group, Swedish multi-centre pilotstudy was carried out. The study was open with regard to the drugs underevaluation but was blind for the patients, all personnel at the studysites, and for the person monitoring the experiments with regard to thedoses of melagatran and the prodrug of melagatran,EtOOC—CH₂—(R)Cgl-Aze-Pab-OH (P; see WO 97/23499).

Dalteparin (Fragmin®; Pharmacia-Upjohn) was used as a referencecompound.

Patients scheduled for primary elective total hip or knee replacementwere eligible for inclusion, and were randomly selected into one ofthree groups, each to receive different doses of melagatran and P, ordalteparin. In all, 135 patients were included in the study, of which105 patients could be used for evaluation with respect to thromboembolicevents using central assessment of locally performed phlebograms.

About 32 patients in each treatment group were evaluated according tothe protocol. A stratified randomisation, by centre and type of surgery,was used to ensure that approximately equal numbers of patients weregiven each of the drugs under evaluation at all participating centres(in all six centres were used) for both types of surgery (hip or knee).Each centre received study drugs in blocks of four, separately for hipsand knees. Within each block, the order of the study drugs wasrandomised.

The following formulations were used in the study:

Melagatran—5, 10 or 20 mg/mL in aqueous saline solution.

P—appropriate weight (see below) in a tablet also comprising 59 to 63 mgcorn starch, 115 mg microcrystalline cellulose and 2 mg sodium stearylfumarate.

The following doses of melagatran and P were used in the study:

Treatment A—s.c. melagatran (1 mg) b.i.d. for 2 days, followed by oraladministration of P (6 mg) b.i.d. for 6 to 9 days.

Treatment B—s.c. melagatran (2 mg) b.i.d. for 2 days, followed by anoral administration of P (12 mg) b.i.d. for 6 to 9 days.

Treatment C—s.c. melagatran (4 mg) b.i.d. for 2 days, followed by anoral administration of P (24 mg) b.i.d. for 6 to 9 days.

The patients receiving melagatran and P received treatment on the day ofsurgery. The patient received the first injection after induction ofanaesthesia immediately before surgery. For knee-patients, thepre-operative melagatran injection was given before tourniquets wereapplied. The second injection was given in the evening the same day. Thepatient received one melagatran injection in the morning and one in theevening over the next 24 hours, until oral administration of P, twicedaily, started. The first oral dose of P was always taken in themorning. Thus, the total treatment period was between 8 and 11 days.

Treatment D—dalteparin (Fragmin®): one s.c. injection of 5000 U duringthe evening of the day before surgery, continuing with one s.c.injection every evening over a treatment period of 8 to 11 days.

The plasma concentrations of melagatran were recorded.

The results of the trial, in terms of the frequencies of thromboembolismafter hip or knee surgery, are tabulated below: Treatment TreatmentTreatment Treatment A B C D (n) (%) (n) (%) (n) (%) (n) (%) Outcome 6/2921 6/24 25 4/24 16 5/27 19

These data show that a combination of subcutaneously administeredmelagatran and orally administered P is effective in preventing DVTafter orthopaedic surgery.

1. A kit of parts comprising: (a) a pharmaceutical formulation includinga low molecular weight thrombin inhibitor, or a pharmaceuticallyacceptable derivative thereof, in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier; and (b) a pharmaceuticalformulation including a prodrug of a low molecular weight thrombininhibitor, or a pharmaceutically acceptable derivative of that prodrug,in admixture with a pharmaceutically acceptable adjuvant, diluent orcarrier, which components (a) and (b) are each provided in a form thatis suitable for administration in conjunction with the other.
 2. A kitof parts as claimed in claim 1, wherein the prodrug of component (b) isa prodrug of the thrombin inhibitor of component (a).
 3. A kit of partsas claimed in claim 1, wherein components (a) and (b) are suitable forsequential, separate and/or simultaneous use in the treatment of acondition in which inhibition of thrombin is required or desired.
 4. Akit of parts as claimed in claim 3, wherein the condition is deep venousthrombosis.
 5. A kit of parts as claimed in claim 1, wherein thethrombin inhibitor is melagatran.
 6. A kit of parts as claimed in claim5, wherein the prodrug is of the formulaR¹O₂C—CH₂—(R)Cgl-Aze-Pab-OH,wherein R¹ represents linear or branchedC₁₋₆ alkyl and the OH group replaces one of the amidino hydrogens inPab.
 7. A kit of parts as claimed in claim 6, wherein R¹ representsmethyl, ethyl or propyl.
 8. A kit of parts as claimed in claim 1,wherein the formulation comprising thrombin inhibitor, or derivativethereof, is a parenteral formulation and that comprising the prodrug, orderivative thereof, is an oral formulation.
 9. A method of making a kitof parts as defined in claim 1, which method comprises bringing acomponent (a) according to claim 1, into association with a component(b) according to claim 1, thus rendering the two components suitable foradministration in conjunction with each other.
 10. A kit of partscomprising: (1) one of components (a) and (b) as defined in claim 1;together with (2) instructions to use that component in conjunction withthe other of the two components.
 11. A pharmaceutical formulationincluding a low molecular weight thrombin inhibitor (or apharmaceutically acceptable derivative thereof) and a prodrug of a lowmolecular weight thrombin (or a pharmaceutically acceptable derivativeof that prodrug), in admixture with a pharmaceutically acceptableadjuvant, diluent or carrier.
 12. A method of treatment of a conditionin which inhibition of thrombin is required or desired, which comprisesadministration of: (a) a pharmaceutical formulation including a lowmolecular weight thrombin inhibitor, or a pharmaceutically acceptablederivative thereof, in admixture with a pharmaceutically acceptableadjuvant, diluent or carrier; in conjunction with (b) a pharmaceuticalformulation including a prodrug of a low molecular weight thrombininhibitor, or a pharmaceutically acceptable derivative of that prodrug,in admixture with a pharmaceutically acceptable adjuvant, diluent orcarrier, to a patient suffering from, or susceptible to, such acondition.
 13. A method as claimed in claim 12 in which component (a) isadministered prior to commencement of administration of component (b).14. A method of treatment of a condition in which inhibition of thrombinis required or desired, which comprises administration of a formulationas defined in claim 11 to a patient suffering from, or susceptible to,such a condition.
 15. A method as claimed in any one of claims 12 to 14,wherein the condition is deep venous thrombosis.
 16. A method as claimedin claim 15, wherein the thrombosis results from surgery.
 17. A methodas claimed in claim 16, wherein the surgery is gastrointestinal surgeryor orthopaedic surgery.
 18. A method as claimed in claim 16, whereincomponent (a) is administered parenterally prior to and/or after surgeryand component (b) is administered orally following that surgery.
 19. Theuse of a thrombin inhibitor, or a pharmaceutically acceptable derivativethereof, in the manufacture of a medicament for the treatment orprophylaxis of a condition in which inhibition of thrombin is requiredor desired, which treatment or prophylaxis comprises administration of:(a) a pharmaceutical formulation including a low molecular weightthrombin inhibitor, or a pharmaceutically acceptable derivative thereof,in admixture with a pharmaceutically acceptable adjuvant, diluent orcarrier; in conjunction with (b) a pharmaceutical formulation includinga prodrug of a low molecular weight thrombin inhibitor, or apharmaceutically acceptable derivative of that prodrug, in admixturewith a pharmaceutically acceptable adjuvant, diluent or carrier, to apatient suffering from, or susceptible to, such a condition.